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Thymicpeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections

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Thymicpeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections International Journal of Molecular Sciences Article ThymicPeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections Anna Hymos 1,*, Ewelina Grywalska 2,3 , Janusz Klatka 1, Maria Klatka 4, Izabela Korona-Głowniak 5 and Jacek Roli ´nski 2,3 1 Department of Otolaryngology and Laryngeal Oncology, Medical University of Lublin, 20-954 Lublin, Poland; [email protected] 2 Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; [email protected] (E.G.); [email protected] (J.R.) 3 Department of Immunology, St. John’s Cancer Centre, Lublin 20-090, Poland 4 Department of Pediatric Endocrinology and Diabetology, Medical University, 20-093 Lublin, Poland; [email protected] 5 Department of Pharmaceutical Microbiology, Medical University, 20-093 Lublin, Poland; [email protected] * Correspondence: [email protected]; Tel.: + 48-81448-6420 Received: 22 February 2020; Accepted: 29 March 2020; Published: 30 March 2020 Abstract: Recurrent infection with human alphaherpesvirus 1 (HHV-1) may be associated with immune exhaustion that impairs virus elimination. Thymic peptides enhance immune function and thus could overcome immune exhaustion. In this study, we investigated whether reactivation of herpes infections was associated with immune exhaustion. Moreover, we examined the impact of treatment with thymostimulin on the expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) on T and B lymphocytes in patients suffering from recurrent HHV-1 reactivation. We also assessed the effector function of peripheral blood mononuclear cells (PBMCs) after stimulation with thymic peptides. We enrolled 50 women with reactivated HHV-1 infections and healthy volunteers. We measured the expression of various activation and exhaustion markers on the surface of PBMCs using flow cytometry. In ex vivo experiments, we measured the secretion of inflammatory cytokines by PBMCs cultured with thymostimulin. Compared with controls, patients with reactivated HHV-1 infections had increased percentages of CD3+ co-expressing CD25, an activation marker (p < 0.001). Moreover, these patients had increased percentages of CD4+ and CD8+ cells co-expressing the inhibitory markers PD-1 and PD-L1. In cultures of PBMCs from the patients, thymostimulin increased the secretion of interferon gamma (p < 0.001) and interleukin (IL)-2 (p = 0.023), but not IL-4 or IL-10.Two-month thymostimulin therapy resulted in no reactivation of HHV-1 infection during this period and the reduction of PD-1 and PD-L1 expression on the surface of T and B lymphocytes (p < 0.001). In conclusion, reactivation of herpes infection is associated with immune exhaustion, which could be reversed by treatment with thymic peptides. Keywords: herpes simplex; immune exhaustion; programmed cell death protein 1; thymic peptides 1. Introduction Human alphaherpesvirus 1 (HHV-1) is a common pathogen; nearly 80% of people aged 22–30 years have anti-HHV-1 antibodies, and the incidence increases with age [1,2]. Mucocutaneous lesions are the most common symptom of HHV-1 infections [3]. After the first infection, HHV-1 persists in neurons, and the infection can recur with or without symptoms [4,5]. Immunocompetent people combat HHV-1 Int. J. Mol. Sci. 2020, 21, 2379; doi:10.3390/ijms21072379 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 2379 2 of 11 infections without antiviral medications, whereas those with impaired immunity can have severe infections despite treatment [6]. Viral infections affect the immune function. T cells launch antiviral responses during acute infections, whereas chronic infection can cause T-cell exhaustion [7]. Exhausted T cells display a reduced production of antiviral cytokines, decreased cytotoxicity, and an impaired immediate response to previously encountered viral antigens [7]. Antigen stimulation activates lymphocytes, but it also increases the expression of programmed cell death protein 1 (PD-1), an inhibitory immune protein. The binding of PD-1 to programmed death ligand 1 (PD-L1) regulates the response to antigens [8]; it reduces the immune response and enhances tolerance to foreign antigens, increasing the risk of chronic infections [9]. Different thymic peptides enhance immune function [10]. Thymosin alpha and prothymosin alpha are among the best-studied thymic peptides [11]. Thymosin inhibits the replication of HHV-1 [12], and it increases the major histocompatibility complex(MHC)-mediated presentation of viral antigens on the cell surface for enhanced recognition of infected cells [13,14]. Moreover, thymosin alpha stimulates the production of interferon gamma (IFN-γ), interleukin (IL)-7, and IL-15, thereby increasing the number of T helper cells (Th), cytotoxic T cells, and natural killer (NK) cells [13,15]. The aim of this study was to measure the percentages of CD4+ and CD8+ cells co-expressing PD-1 and PD-L1 in patients with reactivated HHV-1 infections and to investigate the ability of immune cells to produce cytokines after stimulation with thymic peptides. We hypothesized that reactivation of herpes infections would be associated with the appearance of lymphocyte exhaustion markers on lymphocytes and that thymic peptides would stimulate antiviral responses in peripheral blood mononuclear cells (PBMCs). 2. Results 2.1. Participants We enrolled 50 women with reactivated HHV-1 infections (age range: 19–66 years; mean age ± standard deviation (SD): 41.21 12.42 years). Twenty volunteers served as a control group (age range: ± 18–69 years; mean age SD:42.87 15.81 years). Table1 presents the characteristics of the patients. ± ± Table 1. Characteristics of patients with reactivated human alphaherpesvirus 1 (HHV-1) infections and controls. Variable Statistics Patients (n = 50) Controls (n = 20) median (min–max) 40.05 (19–66) 44 (18–69) Age (years) mean SD 41.21 12.42 42.87 15.81 ± ± ± Yes 8 (16%) 0 anti-HHV-1IgM, n (%) No 42 (84%) 20 (100%) median (min–max) 27.72 (12.11–62.7) - anti-HHV-1 IgM, U/mL mean SD 27.45 18.33 - ± ± Yes 50 (100%) 0 anti-HHV-1IgG, n (%) No 0 20 (100%) median (min–max) 70.62 (22.41–1701.82) - anti-HHV-1 IgG, U/mL mean SD 167.09 301.18 - ± ± Yes 0 0 anti-HHV-2IgM, n (%) No 50 (100%) 20 (100%) Yes 0 0 anti- HHV-2 IgG, n (%) No 50 (100%) 20 (100%) Int. J. Mol. Sci. 2020, 21, 2379 3 of 11 2.2. Frequencies of Basic Lymphocyte Subsets in Patients with Reactivated HHV-1 Infections and Controls We assessed the frequencies of basic lymphocyte subsets in patients with reactivated HHV-1 infection and the control group. Patients exhibited significantly lower percentages ofCD19+ B cells than controls (p = 0.002, Table2). Moreover, in the group of patients with reactivated HHV-1 infection, we found higher frequencies of CD4+CD25+highFOXP3+ T regulatory (Treg) cells and NK cells (p < 0.001, p < 0.025, respectively, Table2). Table 2. Subpopulation of lymphocytes in patients with reactivated HHV-1 infections before and after thymostimulin therapy (TFX),and the control group. Patients with Reactivated Control p (Patients before p (Patients Variable HHV-1 Infections (n = 50) Group TFX vs. Controls) before vs. before TFX after TFX (n = 20) after TFX) median 69.62 73.66 71.94 CD3+ (min–max) (62.55–74.97) (62.23-83.19) (61.61–74.53) NS 0.001 T lymphocytes (%) mean SD 69.31 3.35 73.31 4.29 70.44 3.53 ± ± ± ± median 10.44 15.31 13.62 CD19+ B lymphocytes (min–max) (6.12–16.96) (0.29–19.46) (8.69–16.88) 0.002 <0.001 (%) mean SD 10.60 3.22 13.95 4.12 13.33 2.46 ± ± ± ± CD4+CD3+ T median 39.16 40.25 38.34 lymphocytes (min–max) (25.19–59.88) (23.07–55.45) (33.40–57.43) NS NS mean SD 39.92 6.62 38.76 9.36 41.06 6.36 (%) ± ± ± ± CD8+CD3+ T median 29.42 28.81 27.71 lymphocytes (min–max) (11.17–49.29) (9.01–52.22) (12.78–37.16) NS NS mean SD 28.62 7.07 31.04 11.35 28.48 6.10 (%) ± ± ± ± median 1.29 1.49 1.34 CD4+CD3+/CD8+CD3+ (min–max) (0.51–4.86) (0.50–6.15) (0.92–4.49) NS NS ratio mean SD 1.58 0.84 1.57 1.04 1.58 0.79 ± ± ± ± median 17.77 10.19 14.26 NK cells (min–max) (10.16–27.72) (3.43–18.56) (9.16–24.08) 0.025 <0.001 (%) mean SD 17.51 3.85 10.30 3.96 15.09 4.42 ± ± ± ± median 4.19 4.31 3.29 NKT-like cells (%) (min–max) (0.84–16.06) (0.91–17.83) (1.86–4.91) 0.048 NS mean SD 5.21 3.35 5.43 3.33 3.30 1.02 ± ± ± ± T regulatory cells median 6.61 6.63 4.26 (CD4+CD25+ (min–max) (3.13–16.85) (3.11–13.66) (3.23–7.45) <0.001 0.020 mean SD 8.32 3.82 7.10 2.72 4.45 1.06 FOXP3) (%) ± ± ± ± SD: standard deviation; NS: not significant; TFX: thymostimulin therapy. 2.3. Frequencies of CD25+, PD-1+, and PD-L1+ T and B Lymphocytes in Patients with Reactivated HHV-1 Infections and Controls Patients with reactivated HHV-1 infections had a significantly higher percentage of CD3+CD25+ cells than did the controls (p < 0.001, Table3). Moreover, the percentages of CD4 + cells and CD8+ cells co-expressing PD-1 were higher in patients with reactivated HHV-1 infections than in the control group (p < 0.001 for both comparisons). The percentages of CD4+ cells and CD8+ cells co-expressing PD-L1 were increased in patients with recurrent HHV-1 infections compared with the control group (p < 0.001 for both comparisons, Table3).
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